Screening for Tumor Microtube–Targeting Drugs Identifies PKC Modulators as Multipotent Inhibitors of Glioblastoma Progression
Year: 2025
Type: article
Abstract: Glioblastomas are incurable primary brain tumors that depend on neural-like cellular processes, tumor microtubes (TM), to invade the brain. TMs also interconnect single tumor cells to a communicating multicellular network that resists current therapies. In this study, we developed a combined, comprehensive in vitro/in vivo anti-TM drug screening approach, including machine learning-based analysis tools. Two protein kinase C (PKC) modulators robustly inhibited TM formation and pacemaker tumor cell-driven, TM-mediated glioblastoma cell network communication. As TM-unconnected tumor cells exhibited increased sensitivity to cytotoxic therapy, the PKC activator TPPB was combined with radiotherapy, and long-term intravital two-photon microscopy paired with spatially resolved multiomics revealed anti-TM and antitumor effects. TPPB treatment also decreased the expression of tweety family member 1 (TTYH1), a key driver of invasive TMs. Our study establishes a novel screening pipeline for anti-TM drug development, identifies a TM master regulator pathway, and supports the approach of TM targeting for efficient brain tumor therapies. SIGNIFICANCE: Cancers can hijack neural properties to grow, disseminate, and to resist therapies, but effective drug development pipelines against these features are missing. Here, we establish a compound screening approach that allowed the identification of PKC modulators that target cancer cell-intrinsic neurodevelopmental mechanisms, suggesting a new class of neuroscience-instructed cancer therapeutics.
Source: Cancer Discovery
Authors: Daniel D. Azorín, Dirk C. Hoffmann, Nils R. Hebach, Erik Jung, David Hausmann, Miriam Ratliff, Ling Hai, Sandra Horschitz, Ammar Jabali, Matthias Osswald, Matthia A. Karreman, Tobias Kessler, Susann Wendler, Chanté D. Mayer, Cathrin Löb, Pascal Lehnert, Gina Cebulla, Denise Reibold, Rajiv K. Khajuria, Pino Bordignon, Andreas E. Moor, Tim Holland-Letz, Jill Reckless, Nigel Ramsden, David Grainger, Anna Kreshuk, Philipp Koch, Wolfgang Wick, Sophie Heuer, Frank Winkler
Institutions: German Cancer Research Center, Heidelberg University, ETH Zurich, National Center for Tumor Diseases, Deutsches Konsortium für Translationale Krebsforschung, University Hospital Heidelberg, University Medical Centre Mannheim, Medizinische Fakultät Mannheim, Central Institute of Mental Health, R&D Systems (United States), European Molecular Biology Laboratory, European Molecular Biology Laboratory
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4414985969